Role Of Fibroblast Growth Factor 21 Research Articles

The role of FGF21 in the interplay between obesity and non-alcoholic fatty liver disease: a narrative review.

Obesity poses a significant and escalating challenge in contemporary society, increasing the risk of developing various metabolic disorders such as dyslipidemia, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and certain types of cancer. The current array of therapeutic interventions for obesity remains insufficient, prompting a pressing demand for novel and more effective treatments. In response, scientific attention has turned to the fibroblast growth factor 21 (FGF21) due to its remarkable and diverse impacts on lipid, carbohydrate, and energy metabolism. This comprehensive review aims to delve into the multifaceted aspects of FGF21, encompassing its discovery, synthesis, functional roles, and potential as a biomarker and therapeutic agent, with a specific focus on its implications for NAFLD.

The role of fibroblast growth factor 21 in metabolic processes in patients with gastrointestinal diseases

Background. Recently, the number of patients with obesity and metabolic syndrome has increased. Numerous studies to find new regulators of metabolic processes have led to the disco­very of a new fibroblast growth factor 21 (FGF21). The purpose of the study was to determine the correlation between FGF21 and meta­bolic processes among patients with gastrointestinal pathology. Materials and methods. The study was conducted in 80 patients with gastrointestinal diseases aged 18 to 66 years, the average age was (39.04 ± 1.03) years. Among the subjects, there were 56 men (70.0 %) and 24 women (30.0 %). Body composition was assessed using the Tanita MC-780MA apparatus (Japan). Serum leptin, FGF21, insulin levels were measured by enzyme-linked immunosorbent assay, and the HOMA-IR was calculated. Free fatty acids in the serum of patients were evaluated on Chromateс Crystal-5000, a gas chromatograph with a flame ionization detector. Results. The study found positive correlations between FGF21 levels and indicators of bioimpedance analysis: body mass index (r = 0.24; p = 0.004), fat mass (r = 0.26; p = 0.01) and visceral fat (r = 0.29; p = 0.01). In addition, a relationship was detected between FGF21 levels and laboratory data: insulin (r = 0.32; p = 0.001), HOMA-IR (r = 0.31; p = 0.001), leptin (r = 0.32; p = 0.001), triglyceride/high-density lipoprotein ratio (r = 0.48; p = 0.0001), and the content of certain free fatty acids. This indicates that FGF21 affects the development of obesity and metabolic disorders. It was found that FGF21 is associated with visceral obesity in patients with digestive diseases (odds ratio = 1.28, p = 0.0022). FGF21 levels above 1,317.5 pg/mL (sensitivity of 71.0 %, specificity of 53.1 %) indicate the presence of visceral obesity in patients with gastrointestinal di­seases. Conclusions. As a result of a comprehensive study, new data were obtained on the role of FGF21 as a key regulator of metabolic disorders, which is confirmed by the established relationships of this indicator with the components of lipid and carbohydrate metabolism disorders, cytokine imbalance, and hormonal activity of adipose tissue in patients with pathology of the digestive system.

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21

Non-alcoholic fatty liver disease (NAFLD) has been shown to influence breast cancer progression, but the underlying mechanisms remain unclear. In this study, we investigated the impact of NAFLD on breast cancer tumor growth and cell viability through the potential mediator, hepatic fibroblast growth factor 21 (FGF21). Both peritumoral and systemic administration of FGF21 promoted breast cancer tumor growth, while FGF21 knockout attenuated the tumor-promoting effects of the high-fat diet. Mechanistically, exogenous FGF21 treatment enhanced the anti-apoptotic ability of breast cancer cells through STAT3 and Akt/FoXO1 signaling pathways, and mitigated doxorubicin-induced cell death. Furthermore, we observed overexpression of FGF21 in tumor tissues from breast cancer patients, which was associated with poor prognosis. These findings suggest a novel role for FGF21 as an upregulated mediator in the context of NAFLD, promoting breast cancer development and highlighting its potential as a therapeutic target for cancer treatment.

Fibroblast Growth Factor 21 Has a Diverse Role in Energetic and Reproductive Physiological Functions of Female Beef Cattle.

Fibroblast growth factor 21 (FGF21) has been identified in multiple mammalian species as a molecular marker of energy metabolism while also providing negative feedback to the gonads. However, the role of FGF21 in regulating the energetic and reproductive physiology of beef heifers and cows has yet to be characterized. Herein, we investigated the temporal concentrations of FGF21 in female beef cattle from the prepubertal period to early lactation. Circulating concentrations of FGF21, non-esterified fatty acids, plasma urea nitrogen, glucose, and progesterone were assessed. Ultrasonography was employed to determine the onset of puberty and resumption of postpartum ovarian cyclicity as well as to measure backfat thickness. Finally, cows and calves underwent the weigh-suckle-weigh technique to estimate rate of milk production. We have revealed that FGF21 has an expansive role in the physiology of female beef cattle, including pubertal onset, adaptation to nutritional transition, rate of body weight gain, circulating markers of metabolism, and rate of milk production. In conclusion, FGF21 plays a role in physiological functions in beef cattle that can be applied to advance the understanding of basic scientific processes governing the nutritional regulation of reproductive function but also provides a novel means for beef cattle producers to select parameters of financial interest.

FGF19 promotes nasopharyngeal carcinoma progression by inducing angiogenesis via inhibiting TRIM21-mediated ANXA2 ubiquitination

PurposeNasopharyngeal carcinoma (NPC) has characteristics of high invasion and early metastasis. Most NPC patients present with locoregionally advanced illness when first diagnosed. Therefore, it is urgent to discover NPC biomarkers. Fibroblast growth Factor 19 (FGF19) plays a role in various physiological or pathological processes, including cancer. In this research, we discovered the importance of FGF19 in NPC, and clarified its role in tumour angiogenesis.MethodsWestern blotting, immunohistochemistry and ELISA were used to investigate FGF19 expression in NPC. Then we took CCK8, colony formation, Transwell and wound healing assays to identify the influence of FGF19 on NPC malignant behaviours. The proliferative and metastatic capacity of FGF19 were evaluated in nude mice and zebrafish. The role of FGF19 in angiogenesis was investigated by tube formation and Matrigel plug angiogenesis assays. We then evaluated the variation in Annexin A2(ANXA2) levels with the treatment of FGF19. Lastly, co-immunoprecipitation and ubiquitination assays were performed to identify the mechanisms involved.ResultsFGF19 levels were elevated in tissues and serum of NPC patients and were associated with poor clinical stages. High expression of FGF19 promoted NPC malignant behaviours. In particular, FGF19 expression was correlated with microvessel density in tissues and NPC-derived FGF19 could accelerate angiogenesis in vitro and in vivo. Mechanistically, FGF19 influenced ANXA2 expression to promote angiogenesis. Moreover, tripartite motif-containing 21(TRIM21) interacted with ANXA2 and was responsible for ANXA2 ubiquitination.ConclusionFGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.

Fibroblast growth factor 21 may be a strong biomarker for renal outcomes: a meta-analysis

Background Fibroblast growth factor 21 (FGF21) is deemed to play an important role in kidney outcomes, while the association between FGF21 and various kidney diseases remains largely unclear and inconsistent. Therefore, we conducted this meta-analysis to find out the role of FGF21 in various renal diseases. Methods The outcome indicator of our study was assessed by the pooled standard mean difference (SMD) with 95% confidence intervals (CIs) which were calculated by random-effect model analysis. The risk of bias was assessed by Non-Randomized Studies of Interventions (ROBINS-I) tool. Funnel plot combined with Egger’s and Begg’s tests was performed to estimate the publication bias that existed in the study. Results A total of 28 eligible studies with 19348 participants were included in our research. The agreement between authors reached a kappa-value of 0.88. Overall, the serum FGF21 level was strongly higher in CKD patients (SMD = 0.97 (ng/L); 95% CI, 0.70—1.24 (ng/L)) and the renal outcomes in T2DM patients (SMD = 0.54 (ng/L); 95% CI, 0.39–0.70 (ng/L)) compared with the control group. Consistent with this, the incidence of CKD (OR = 2.56; 95% CI, 1.72–3.81) and the incidence of renal outcomes (OR = 1.63; 95% CI, 1.31–2.01) in T2DM patients was significantly higher in the patients with high FGF21 concentration, indicating that high serum FGF21 level may predict the incidence of CKD and the renal outcomes in T2DM patients. Conclusion Serum FGF21 may be one of the strong predictors for various kidney diseases including the progression of CKD and the hard renal outcomes in type 2 diabetes patients, but more large-scale clinical research are needed to confirm this finding.

Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: A meta-analysis.

The role of fibroblast growth factor 21 (FGF21) in predicting the long-term prognosis of patients with cardiovascular disease (CVD) remains unknown. A comprehensive search in PubMed, Embase, and the Cochrane Library was performed to identify studies reporting the association between FGF21 and prognosis among patients with CVD. A meta-analysis was performed, with patients stratified by coronary artery disease (CAD) or heart failure (HF). The endpoint of CAD or HF was major adverse cardiovascular events defined by each study and a composite of death or HF readmission, respectively. The I2 method and linear regression test of funnel plot asymmetry were used to test heterogeneity (I2 > 50% indicates substantial heterogeneity) and publication bias (asymmetry P < 0.05, indicating publication bias). A total of 807 records were retrieved, and nine studies were finally included. Higher FGF21 levels were significantly associated with the risk of major adverse cardiovascular events in patients with CAD (multivariate hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.40-2.23, P < 0.05, I2 = 0%, fixed-effect model). Increased FGF21 levels were also associated with the risk of all-cause death among patients with CAD (multivariate HR: 2.67, 95% CI: 1.25-5.72, P < 0.05, I2 = 64%, random-effect model). No association was found between FGF21 and the endpoint among patients with HF (HR: 1.57, 95% CI: 0.99-2.48, P > 0.05, random-effect model), but a large heterogeneity (I2 = 95%) and potential publication bias (Asymmetry P < 0.05) existed in the analysis. Increased FGF21 levels were independently associated with poor prognosis of CAD, whereas the role of FGF21 in predicting clinical outcomes of HF requires further investigation.

Fibroblast Growth Factor 21 Levels and Bone Mineral Density in Metabolically Healthy and Metabolically Unhealthy Obese Children

The harmful or beneficial effect of obesity on bone mineral density (BMD) remains controversial in children and adolescents. Fibroblast growth factor 21 (FGF21) is a metabolic factor that plays a specific role in the regulation of carbohydrate and lipid metabolism. However, the role of FGF21 in bone metabolism appears paradoxical and is complex. To determine whether serum FGF21 level was associated with BMD in obese children and adolescents. The study was conducted with the participation of children and adolescents aged 8-18 years. Ninety-eight obese children were included in the study group and 44 children were included in the control group. BMD, in addition to the routine obesity workup, which includes fasting blood glucose, fasting insulin levels, lipid profile, and liver enzymes; serum FGF21 levels have been analyzed. The mean age of the obese group (n=98) was 13.34±2.24 years and the mean age of controls (n=44) was 13.48±2.87 years. Based on International Diabetes Federation criteria, 15 of 98 (15.3%) patients were metabolically unhealthy. FGF21 levels were 193.54±139.62 mg/dL in the obese group and 158.69±151.81 mg/dL in the control group (p=0.06). There was no difference between the FGF21 and BMD z-score values of girls and boys in the obese and control groups (p>0.05). BMD-z-score was increased in obese children compared to healthy control. Moreover, BMD-z-score tended to be higher when more metabolic risk factors were present. However, there was no significant relationship between FGF21 levels and BMD z-score values in obese children.

The role of FGF21 and its analogs on liver associated diseases.

Fibroblast growth factor 21 (FGF21), a member of fibroblast growth factor family, is a hormone-like growth factor that is synthesized mainly in the liver and adipose tissue. FGF21 regulates lipid and glucose metabolism and has substantial roles in decreasing lipogenesis and increasing hepatic insulin sensitivity which causing lipid profile improvement. FGF21 genetic variations also affect nutritional and addictive behaviors such as smoking and alcohol consumption and eating sweets. The role of FGF21 in metabolic associated diseases like diabetes mellitus had been confirmed previously. Recently, several studies have demonstrated a correlation between FGF21 and liver diseases. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease worldwide. NAFLD has a wide range from simple steatosis to steatohepatitis with or without fibrosis and cirrhosis. Elevated serum levels of FGF21 associated with NAFLD and its pathogenesis. Alcoholic fatty liver disease (AFLD), another condition that cause liver injury, significantly increased FGF21 levels as a protective factor; FGF21 can reverse the progression of AFLD and can be a potential therapeutic agent for it. Also, NAFLD and AFLD are the most important risk factors for hepatocellular carcinoma (HCC) which is the fourth deadliest cancer in the world. Several studies showed that lack of FGF21 induced oncogenic condition and worsened HCC. In this review article, we intend to discuss different aspects of FGF21 in NAFLD, AFLD and HCC; including the role of FGF21 in pathophysiology of these conditions, the effects of FGF21 mutations, the possible use of the FGF21 as a biomarker in different stages of these diseases, as well as the usage of FGF21 and its analog molecules in the treatment of these diseases.

Fibroblast growth factor 21 is independently associated with long term mortality in metabolic syndrome

Abstract Background Metabolic syndrome (MetS), a cluster of interrelated cardiovascular risk factors, is associated with increased risk of cardiovascular and non-cardiovascular disease. Fibroblast growth factor 21 (FGF21) plays an important role in metabolic regulation and has been shown to be elevated in MetS. However, role of FGF21 in pathogenesis of cardiovascular disease is still controversial. Objective We aimed to identify the association between plasma FGF21 level and long-term mortality in MetS patients. Methods Patients with MetS were enrolled in this study during 2015–2017. Blood samples for FGF21 were collected after 12-hour fasting and plasma FGF21 levels were determined using a human FGF21 enzyme-linked immunosorbent assay (ELISA) at the first time of the enrollment. Clinical parameters, and all-cause mortality were recorded. Cox-proportional hazard regression was used for the analysis of association between plasma FGF21 level and all-cause mortality. Results A total of 202 Mets patients (male 44.6%) with mean age of 64.3±8.3 years and BMI of 27.3±5.4 kg/m2 were enrolled. After a median follow up of 80 months, 32 (15.8%) patients died. Multivariable Cox proportional hazard regression showed that FGF21 level was independently associated with all-cause mortality after adjustment for age, established cardiovascular disease, estimated glomerular filtration rate and left ventricular ejection fraction. Patients with FGF21 level above median (240 pg/ml) had higher risk of all-cause death compared to patients with FGF21 ≤240 pg/ml (hazard ratio [HR], 3.66; 95% confidence interval [CI], 1.24–10.82; p=0.019) (Figure 1). Conclusion FGF21 level is independently associated with long term mortality in metabolic syndrome. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Thailand research fund

Fibroblast growth factor 21 and dietary interventions: what we know and what we need to know next.

Dietary interventions include the change of dietary styles, such as fasting and dietary or nutrient restrictions; orthe addition of plant-derived compounds (such as polyphenols known as curcumin, resveratrol, or anthocyanin, or other nutraceuticals) into the diet. During the past a few decades, large number of studies have demonstrated therapeutic activities of these dietary interventions on metabolic and other diseases in human subjects or various animal models. Mechanisms underlying those versatile therapeutic activities, however, remain largely unclear. Interestingly, recent studies have shown that fibroblast growth factor 21 (FGF21), a liver-derived hormone or hepatokine, mediates metabolic beneficial effects of certain dietary polyphenols aswell as protein restriction. Here I have briefly summarized functions of FGF21, highlighted related dietary interventions, and presented literature discussions on role of FGF21 in mediating function of dietary polyphenol intervention andprotein restriction. This is followed by presenting my perspective view, with the involvement of gut microbiota. It is anticipated that further breakthroughs in this field in the near future will facilitate conceptual merge of classical medicine and modern medicine.

Fibroblast growth factor 21 as a new tool in the multicomponent assessment of cardiovascular diseases

Currently, the search and study of new biological markers that can assist in the early diagnosis of cardiovascular diseases, serving as a laboratory tool for assessing the efficiency of ongoing therapy and being a prognostic criterion of possible clinical outcomes and a significant indicator in risk stratification, remain relevant. Two decades have passed since fibroblast growth factor 21 (FGF21), the 21st member of the FGF family, was identified and cloned. FGF21 is a secreted protein that acts as a metabolic regulator and participates in glucose homeostasis, ketogenesis, and regulation of insulin sensitivity. FGF21 expression is controlled by PPAR alpha receptor, which activates peroxisome proliferation. The liver is the main site of FGF21 production. Extrahepatic tissues such as white adipose tissue, brown adipose tissue, and skeletal muscle also express FGF21. Human FGF21 contains 209 amino acids, whereas the mouse counterpart has 210. Mouse and human FGF21 have 75% homology. Endocrine actions of FGF21 include enhancing glucose uptake by adipocytes of white adipose tissue via a unidirectional glucose transporter protein and activating the thermogenic function of brown adipose tissue. Furthermore, FGF21 has autocrine/paracrine effects, such as the induction of hepatic ketogenesis. FGF21 affects target cells with the participation of FGFR1 and FGFR4 receptors and beta-Klotho, a single-pass transmembrane protein that functions as an obligate cofactor of FGF21 signaling. Animal studies have clearly demonstrated that FGF21 acts directly on cardiac tissue, preventing the development of cardiac hypertrophy and reducing post-infarction damage and diabetic cardiomyopathy. Accumulating data emphasize the value of FGF21 as a new biological marker for diagnosis and prognosis assessment in patients with cardiac issues. Moreover, the role of FGF21 in heart diseases is very interesting because of its cardioprotective effects. Future large-scale prospective studies are necessary to confirm of the diagnostic, predictive, and possibly therapeutic role of this marker.

Fibroblast growth factor 21 is related to cisplatin resistance in ovarian cancer.

Fibroblast growth factor 21 is related to cisplatin resistance in ovarian cancer.

Low serm Fibroblast Growth Factor-21 levels is not associated with Carotid intima-media thickness in acromegaly patients.

Elevated fibroblast growth factor-21 (FGF-21) levels are related to carotid intima-media thickness (CIMT), a well-established marker of atherosclerosis. Acromegaly has also been linked to increased CIMT. There has been no data considering the association between FGF-21 levels and atherosclerosis in acromegaly patients. This study aimed to evaluate FGF-21 levels and CIMT in acromegalic patients in relation to atherosclerotic complications. Case-control study. The study group included 70 acromegaly patients and 72 healthy volunteers from the Department of Endocrinology and Metabolism Disease, Marmara University Medical School. FGF-21, growth hormone, insulin-like growth factor I, lipids, glucose, insulin levels were assessed. CIMT was measured from the common carotid artery wall on B-mode ultrasound. Median FGF-21 levels were significantly lower in the acromegaly group than in the control group. CIMT was higher in acromegaly patients compared to controls. Although there was no correlation between FGF-21 levels and CIMT in patients with acromegaly, a positive correlation was found between high-density lipoprotein-cholesterol and FGF-21 levels. Glucose metabolic markers were the determining factors of the FGF-21 levels in acromegaly patients. Our study is the first to examine the relationship between serum FGF-21 levels and atherosclerosis in acromegaly patients. The lower serum FGF-21 levels in acromegaly subjects might be associated with the improving effects of growth hormone on liver fat. Acromegaly was linked to higher CIMT, but there was no correlation between FGF-21 levels and CIMT. The role of FGF-21 in acromegaly as a marker of atherosclerosis requires additional research.

FGF21 attenuates high uric acid‑induced endoplasmic reticulum stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1.

Uric acid (UA) is the final oxidation product of purine metabolism. Hyperuricemia has been previously reported to contribute to vascular endothelial dysfunction and the development of cardiovascular diseases, metabolic syndrome and chronic kidney diseases. In addition, it has been reported that fibroblast growth factor 21 (FGF21) can exert regulatory effects on UA-induced lipid accumulation. Therefore, the present study aimed to investigate the possible role of FGF21 in HUVEC cell injury induced by UA. The study used UA to induce HUVEC cell injury, inhibited sirtuin 1 (Sirt1) expression using EX527 and overexpressed FGF21 by transfection. Subsequently, reverse transcription-quantitative PCR was performed to measure the mRNA expression levels of FGF21, Sirt1 and inflammatory cytokines TNF-α, IL-1β and IL-6, whereas western blotting was performed to measure their corresponding protein expression levels including FGF21, Sirt1, NLR family pyrin domain containing 3, pro-caspase1, apoptosis-associated speck-like protein containing a CARD, activating transcription factor 4, C/EBP homologous protein and eukaryotic initiation factor 2. Furthermore, dichloro-dihydro-fluorescein diacetate staining was performed to measure intracellular reactive oxygen species (ROS) generation in HUVECs. The levels of ROS and nitric oxide were also quantified using commercial assay kits. The results demonstrated that overexpression of FGF21 significantly inhibited UA treatment-induced endoplasmic reticulum (ER) stress, inflammation and oxidative stress in HUVECs. Furthermore, overexpression of FGF21 significantly activated Sirt1. The sirt1 inhibitor, EX527, significantly abrogated the suppressive effects of FGF21 overexpression on ER stress, inflammation and oxidative stress in UA-stimulated HUVECs. To conclude, results of the present study suggested that FGF21 may attenuate UA-induced ER stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1. Therefore, FGF21 may be a potential effective target for the future treatment of vascular endothelial cell dysfunction.

Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21

Chronic stress leads to post-traumatic stress disorder (PTSD) and metabolic disorders including fatty liver. We hypothesized that stress-induced molecular mechanisms alter energy metabolism, thereby promoting hepatic lipid accumulation even after a stress-free recovery period. In this context, we investigated fibroblast growth factor-21 (FGF21) as protective for energy and glucose homeostasis. FGF21 knockout mice (B6.129S6(SJL)-Fgf21tm1.2Djm; FGF21KO) and control mice (C57BL6; WT) were subjected to chronic variable stress. Mice were examined directly after acute intervention (Cvs) and long-term after 3 months of recovery (3mCvs). In WT, Cvs reduced insulin sensitivity and hepatic lipid accumulation, whilst fatty acid uptake increased. FGF21KO mice responded to Cvs with improved glucose tolerance, insulin resistance but liver triglycerides and plasma lipids were unaltered. Hepatic gene expression was specifically altered by genotype and stress e.g. by PPARa and SREBP-1 regulated genes. The stress-induced alteration of hepatic metabolism persisted after stress recovery. In hepatocytes at 3mCvs, differential gene regulation and secreted proteins indicated a genotype specific progression of liver dysfunction. Overall, at 3mCvs FGF21 was involved in maintaining mitochondrial activity, attenuating de novo lipogenesis, increased fatty acid uptake and histone acetyltransferase activity. Glucocorticoid release and binding to the FGF21 promoter may contribute to prolonged FGF21 release and protection against hepatic lipid accumulation. In conclusion, we showed that stress favors fatty liver disease and FGF21 protected against hepatic lipid accumulation after previous chronic stress loading by i) restored physiological function, ii) modulated gene expression via DNA-modifying enzymes, and iii) maintained energy metabolism.

Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway

Osteoarthritis (OA) is a complex condition that involves both apoptosis and senescence and currently cannot be cured. Fibroblast growth factor 21 (FGF21), known for its role as a potent regulator of glucose and energy metabolism, protects from various diseases, possibly by mediating autophagy. In the present study, the role of FGF21 in the progression of OA was investigated in both in vitro and in vivo experiments. In vitro, the results revealed that FGF21 administration alleviated apoptosis, senescence, and extracellular matrix (ECM) catabolism of the chondrocytes induced by tert-butyl hydroperoxide (TBHP) by mediating autophagy flux. Furthermore, CQ, an autophagy flux inhibitor, could reverse the protective effect of FGF21. It was observed that the FGF21-induced autophagy flux enhancement was mediated by the nuclear translocation of TFEB, which occurs due to the activation of the SIRT1-mTOR signaling pathway. The in vivo experiments demonstrated that FGF21 treatment could reduce OA in the DMM model. Taken together, these findings suggest that FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism via autophagy flux upregulation and also reduces OA development in vivo, demonstrating its potential as a therapeutic agent in OA.

Fibroblast Growth Factor 21 Ameliorates NaV1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes.

Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7–10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7–10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

Lower melanoma pulmonary metastatic burden in obese mice: role of FGF-21.

Obesity is a risk factor for malignant melanoma. The lungs are main target organs for metastization and their immune response is a key modulator of this mechanism. The concept that the metastatic potential of some types of cancer is reduced or inhibited by obesity, known as the obesity paradox, drives major concerns on the prognosis of metastasized patients. The aim of this study was to investigate how high-fat diet (HFD)-induced obesity affects melanoma metastization. C57Bl6/J mice were fed with HFD or standard diet for 180 days and inoculated intravenously with B16F10 melanoma cells. Upon 21 days of inoculation, lung tissue of overweight and lean mice was assessed for histology and immunohistochemistry assays. Adipokine antibody arrays were performed in mice serum. In vitro RAW 264.7 macrophage cultures were established and incubated with FGF-21 and/or lipopolysaccharide (LPS). Conditioned media was added to B16F10 cells for viability quantification. HFD-fed mice presented a reduced number of metastases with lower proliferative rates. The high content of inflammatory foci observed in noninoculated obese mice was significantly decreased upon B16F10 inoculation, concurrent with a slight fibrosis reduction. Plasma levels of fibroblast growth factor-21 (FGF-21), an endocrine regulator, were elevated in noninoculated HFD mice and the expression of FGF receptor 1 (FGFR-1) was significantly upregulated after inoculation. FGF-21 reduced melanoma viability in LPS-stimulated macrophages. Altogether, these findings suggest that higher amounts of FGF-21 are able to counterbalance the proinflammatory effects associated with obesity, protecting the lungs from melanoma metastization.

Serum Levels of Fibroblast Growth Factor 19 Correlate with the Severity of Diarrhea and Independently from Intestinal Inflammation in Patients with Inflammatory Bowel Disease or Microscopic Colitis.

In chronic diarrhea patients, massive over-reporting symptom-based criteria for functional bowel disorders are pitfalls. There is currently no objective biomarker that may provide a correct correlation with the severity of chronic diarrhea. To clarify the role of fibroblast growth factor-19 (FGF-19) as a biomarker of objective measurements of the severity of diarrhea in comparison with a patientreported outcome, based on the Bristol Stool Form (BSF) Scale. Consecutive 100 patients with chronic diarrhea underwent standard investigations with laboratory tests, fecal calprotectin (FC), endoscopy with biopsies, and serum FGF-19. All patients and 14 healthy controls completed a diary recording, BSF, and stool frequency. We found that irritable bowel syndrome with diarrhea (IBS-D) n = 21/23 (91%) reported a high number on BSF ≥6, compared to patients with inflammatory bowel diseases (IBD) 56/77 (72%) with BSF ≥ 6 (P = .011). FGF-19 median serum levels were significantly lower in Microscopic colitis (0.010 pg/mL) and IBD patients (0.009 pg/mL) compare to IBS-D (266.9 pg/mL) and high levels in healthy subjects (463 pg/mL) (P < .001). Strong inverse correlation of FGF-19 with the stool frequency/day and stool index was found (r = -0.800, P < .001; r = -0.739, P < .001), independently from disease activity (r = -0.718, P = .001; r = -0.792, P = .001). Serum FGF-19 can become a new biomarker for evaluating the severity of diarrhea with objectively and independently from intestinal inflammation. FC and FGF-19 are predictive biomarkers for the organic cause of diarrhea.